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Uveal melanoma is the most common primary intraocular malignant tumor in adults with 30% to 50% of patients that ultimately succumb to metastatic disease, mainly to the liver.Although new diagnostic and therapeutic tools have been developed during the most recent years, only the eye conservation rate has been achieved, while the survival rate remains poor.The reason for this liver-homing is largely unknown, but it is conceivable that hepatic environmental factors may be implicated in the growth, dissemination, and progression of this malignancy.The insulin-like growth factor (IGF-1) that binds to the IGF-1 receptor (IGF-1R) is mainly produced in the liver.It has been shown to be crucial for tumor transformation, maintenance of malignant phenotype, promotion of cell growth, and prevention of apoptosis.) Metastasis is a process involving many components, including tumor cell adhesion, migration, extracellular matrix (ECM) proteolysis, and invasion.In this study, we aimed to investigate the effects of picropodophyllin (PPP) a specific inhibitor of IGF-1 R on uveal melanoma cell cultures and xenograffs with special focus on mechanisms important for tumor cell invasion.We showed that intraperitoneal injections of PPP, an inhibitor of IGF-1 R, efficiently blocks uveal melanoma growth and in vivo in uveal melanoma xenografts while in vitro reduce drammatically in a dose dependant manner the survival of 3 different uveal melanoma cell lines as shown with cell survival assay.We also used CytoMatrix screening kit, gelatin zymography, matrigel chambers to show that PPP is able to inhibit several mechanisms involved in metastasis, including tumor cell adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, cell migration,and basement membrane and endothelial invasion.Also PPP significantly reduced the number of the micrometastases to the liver.Also we demonstrated that oral administration of PPP completely blocks the growth of uveal melanoma xenografts established from OCM-3 and OCM-8 cells, and was well tolerated by the mice.PPP also reduced expression of IGF1 dependent VEGF in uveal melanoma tumors in a statistically significant way, with p value being 0.006 and 0.03 in 0CM-1 and OCM-8 tumors respectively.This effect and the anti-angiogenic response probably contribute to the high anti-tumor efficacy ofPPP.PPP was also found to be superior to the other anti-tumor agents such as imatinib mesylate,cisplatin, 5-FU and doxorubicin in killing uveal melanoma cells in experiments performed in four different cell lines.We could only detect a limited synergistic effect with some of them in combination with PPP.